Endocannabinoids are lipid chemical mediators that act locally by activating cannabinoid receptors of type 1 (CB1) and type 2 (CB2) receptors. The two most-studied endocannabinoids are anandamide and 2-arachidonoylglycerol (2-AG), which are released from cells immediately after their biosynthesis from phospholipid-derived precursors, and whose action at receptors is controlled by rapid metabolism.
The levels of the endocannabinoids and/or the expression of cannabinoid receptors in tissues vary during acute or chronic pathological conditions. These changes are due to increases in intracellular calcium concentration, changes in metabolic enzyme expression and availability of phospholipid precursors. They potentially lead to a modification of the activity of CB1 and CB2 receptors, and occur selectively in tissues and cells involved in the pathology.
Anandamide and/or 2-AG are initially biosynthesized and released more, or degraded less, during perturbations of cell homeostasis or acute pathological conditions in an attempt to bring back cell homeostasis to its steady state prior to these perturbations. This seems to occur in a strictly site- and time-specific way.
During certain chronic conditions, the levels of endocannabinoids in tissues might be altered in such a way that they start activating cannabinoid receptors for longer, or on cell populations that they were not initially meant to target, or they start interacting with different receptor types. This loss of specificity results in the contribution of endocannabinoids and their receptors to the symptoms and/or progress of certain chronic disorders.
This plasticity of endocannabinoid signalling opened the way to the development of drugs that either boost or counteract the action of endocannabinoids, by inhibiting their inactivation or their binding to receptor, respectively.
Inhibitors of endocannabinoid degradation via fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), and inhibitors of endocannabinoid cellular reuptake are also known as indirect agonists of endocannabinoid receptors. They have proved useful in animal models of inflammatory and neuropathic pain, inflammatory gastrointestinal diseases, epilepsy, neuromotor disorders, Alzheimer's disease and multiple sclerosis, affective disorders (chronic stress, fear, anxiety and depression), emesis and nausea, colorectal and thyroid cancer, and hypertension.
CB1 antagonists/inverse agonists are already on the market for the treatment of obesity and related metabolic dysfunctions. They are also potentially useful against alcohol and nicotine abuse and drug of abuse reinstatement, Parkinson's and Alzheimer's diseases, liver fibrosis, pernicious hypotensive states induced by septic shock and cirrhosis, inflammatory pain and inflammation, osteoporosis and some cardiopathies. CB2 antagonists/inverse agonists are being tested in animals against inflammation and contact dermatitis and some neuroinflammatory disorders.
Owing to the local action of endocannabinoids, both enhancers and inhibitors of their activity are specifically acting only when and where anandamide and/or 2-AG are being produced and degraded. Therefore, they should exhibit a relatively safe profile of side effects. In view of the pleiotropic effects of endocannabinoids, it is clear that compounds that manipulate either their lifespan or action need to be administered with caution and by making sure to use the appropriate dosage and to select the right patient in the right disease phase.
As our understanding of the endocannabinoids improves, so does the awareness of their complexity. During pathological states, the levels of these mediators in tissues change, and their effects vary from those of protective endogenous compounds to those of dysregulated signals. These observations led to the discovery of compounds that either prolong the lifespan of endocannabinoids or tone down their action for the potential future treatment of pain, affective and neurodegenerative disorders, gastrointestinal inflammation, obesity and metabolic dysfunctions, cardiovascular conditions and liver diseases. When moving to the clinic, however, the pleiotropic nature of endocannabinoid functions will require careful judgement in the choice of patients and stage of the disorder for treatment.
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Russo, E. & Guy, G. W. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Med. Hypotheses 66, 234–246 (2006).
Mechoulam, R. Discovery of endocannabinoids and some random thoughts on their possible roles in neuroprotection and aggression. Prostaglandins Leukot. Essent. Fatty Acids 66, 93–99 (2002).
Pertwee, R. G. Cannabinoid pharmacology: the first 66 years. Br. J. Pharmacol. 147 (Suppl. 1), 163–171 (2006).
Di Marzo, V. & Petrosino, S. Endocannabinoids and the regulation of their levels in health and disease. Curr. Opin. Lipidol. 18, 129–140 (2007).
Alexander, S. P. & Kendall, D. A. The complications of promiscuity: endocannabinoid action and metabolism. Br. J. Pharmacol. 152, 602–623 (2007).
Di Marzo, V., Bifulco, M. & De Petrocellis, L. The endocannabinoid system and its therapeutic exploitation. Nature Rev. Drug Discov. 3, 771–784 (2004).
Piomelli, D. The endocannabinoid system: a drug discovery perspective. Curr. Opin. Investig. Drugs. 6, 672–679 (2005).
Hohmann, A. G. & Suplita, R. L. 2nd. Endocannabinoid mechanisms of pain modulation. AAPS J. 8, e693–e708 (2006).
Jhaveri, M. D., Richardson, D. & Chapman, V. Endocannabinoid metabolism and uptake: novel targets for neuropathic and inflammatory pain. Br. J. Pharmacol. 152, 624–632 (2007).
Lambert, D. M. Allergic contact dermatitis and the endocannabinoid system: from mechanisms to skin care. ChemMedChem 2, 1701–1702 (2007).
Bisogno, T. & Di Marzo, V. Short- and long-term plasticity of the endocannabinoid system in neuropsychiatric and neurological disorders. Pharmacol. Res. 56, 428–442 (2007).
Cota, D. CB1 receptors: emerging evidence for central and peripheral mechanisms that regulate energy balance, metabolism, and cardiovascular health. Diabetes Metab. Res. Rev. 23, 507–517 (2006).
Matias, I. & Di Marzo, V. Endocannabinoids and the control of energy balance. Trends Endocrinol. Metab. 18, 27–37 (2007).
Ashton, J. C. & Smith, P. F. Cannabinoids and cardiovascular disease: the outlook for clinical treatments. Curr. Vasc. Pharmacol. 5, 175–185 (2007).
Bifulco, M., Laezza, C., Gazzerro, P. & Pentimalli, F. Endocannabinoids as emerging suppressors of angiogenesis and tumor invasion. Oncol. Rep. 17, 813–816 (2007).
Storr, M. A. & Sharkey, K. A. The endocannabinoid system and gut–brain signalling. Curr. Opin. Pharmacol. 7, 575–582 (2007).
Mallat, A., Teixeira-Clerc, F., Deveaux, V. & Lotersztajn, S. Cannabinoid receptors as new targets of antifibrosing strategies during chronic liver diseases. Expert Opin. Ther. Targets 11, 403–409 (2007).
Pacher, P., Batkai, S. & Kunos, G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol. Rev. 58, 389–462 (2006).
Kirkham, T. C., Williams, C. M., Fezza, F. & Di Marzo, V. Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol. Br. J. Pharmacol. 136, 550–557 (2002).
Hanus, L. et al. Short-term fasting and prolonged semistarvation have opposite effects on 2-AG levels in mouse brain. Brain Res. 983, 144–151 (2003).
Matias, I. et al. Regulation, function, and dysregulation of endocannabinoids in models of adipose and β-pancreatic cells and in obesity and hyperglycemia. J. Clin. Endocrinol. Metab. 91, 3171–3180 (2006).
Jamshidi, N. & Taylor, D. A. Anandamide administration into the ventromedial hypothalamus stimulates appetite in rats. Br. J. Pharmacol. 134, 1151–1154 (2001).
Di Marzo, V. et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410, 822–825 (2001).
Monteleone, P. et al. Blood levels of the endocannabinoid anandamide are increased in anorexia nervosa and in binge-eating disorder, but not in bulimia nervosa. Neuropsychopharmacology 30, 1216–1221 (2005).
Di Marzo, V., Hill, M. P., Bisogno, T., Crossman, A. R. & Brotchie, J. M. Enhanced levels of endogenous cannabinoids in the globus pallidus are associated with a reduction in movement in an animal model of Parkinson's disease. FASEB J. 14, 1432–1438 (2000).
Gubellini P et al. Experimental parkinsonism alters endocannabinoid degradation: implications for striatal glutamatergic transmission. J. Neurosci. 22, 6900–6907 (2002).
van der Stelt, M. et al. A role for endocannabinoids in the generation of parkinsonism and levodopa-induced dyskinesia in MPTP-lesioned non-human primate models of Parkinson's disease. FASEB J. 19, 1140–1142 (2005).
Ferrer, B., Asbrock, N., Kathuria, S., Piomelli, D. & Giuffrida, A. Effects of levodopa on endocannabinoid levels in rat basal ganglia: implications for the treatment of levodopa-induced dyskinesias. Eur. J. Neurosci. 18, 1607–1614 (2003).
Kreitzer, A. C. & Malenka, R. C. Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson's disease models. Nature 445, 643–647 (2007).
Fernandez-Espejo, E. et al. Cannabinoid CB1 antagonists possess antiparkinsonian efficacy only in rats with very severe nigral lesion in experimental parkinsonism. Neurobiol. Dis. 18, 591–601 (2005).
Gonzalez S. et al. Effects of rimonabant, a selective cannabinoid CB1 receptor antagonist, in a rat model of Parkinson's disease. Brain Res. 1073–1074, 209–219 (2006).
van der Stelt, M. et al. Endocannabinoids and β-amyloid-induced neurotoxicity in vivo: effect of pharmacological elevation of endocannabinoid levels. Cell. Mol. Life Sci. 63, 1410–1424 (2006).
Mazzola, C., Micale, V. & Drago, F. Amnesia induced by β-amyloid fragments is counteracted by cannabinoid CB1 receptor blockade. Eur. J. Pharmacol. 477, 219–225 (2003).
Esposito, G. et al. Opposing control of cannabinoid receptor stimulation on amyloid-β-induced reactive gliosis: in vitro and in vivo evidence. J. Pharmacol. Exp. Ther. 322, 1144–1152 (2007).
Ramirez, B. G., Blazquez, C., Gomez del Pulgar, T., Guzman, M. & de Ceballos, M. L. Prevention of Alzheimer's disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J. Neurosci. 25, 1904–1913 (2005).
Benito, C. et al. Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer's disease brains. J. Neurosci. 23, 11136–11141 (2003).
Cabranes, A. et al. Decreased endocannabinoid levels in the brain and beneficial effects of agents activating cannabinoid and/or vanilloid receptors in a rat model of multiple sclerosis. Neurobiol. Dis. 20, 207–217 (2005).
Witting, A. et al. Experimental autoimmune encephalomyelitis disrupts endocannabinoid-mediated neuroprotection. Proc. Natl Acad. Sci. USA 103, 6362–6367 (2006).
Centonze, D. et al., The endocannabinoid system is dysregulated in multiple sclerosis and in experimental autoimmune encephalomyelitis. Brain 130, 2543–2553 (2007).
Maresz, K. et al. Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells. Nature Med. 13, 492–497 (2007). The first study that really clarifies the distinct beneficial roles of the two cannabinoid receptor types in autoimmune neuroinflammation.
Croxford, J. L. et al. Cannabinoid-mediated neuroprotection, not immunosuppression, may be more relevant to multiple sclerosis. J. Neuroimmunol. 193, 120–129 (2007).
Bilsland, L. G. et al. Increasing cannabinoid levels by pharmacological and genetic manipulation delay disease progression in SOD1 mice. FASEB J. 20, 1003–1005 (2006).
Kim, K., Moore, D. H., Makriyannis, A. & Abood, M. E. AM1241, a cannabinoid CB2 receptor selective compound, delays disease progression in a mouse model of amyotrophic lateral sclerosis. Eur. J. Pharmacol. 542, 100–105 (2006).
Shoemaker, J. L., Seely, K. A., Reed, R. L., Crow, J. P. & Prather, P. L. The CB2 cannabinoid agonist AM-1241 prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis when initiated at symptom onset. J. Neurochem. 101, 87–98 (2007).
Marsicano, G. et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature 418, 530–534 (2002). Perhaps the first example of the site- and time-specific activation of the endocannabinoid system following a stressor and with a protective function in the adaptation to new environmental conditions.
Kamprath, K. et al. Cannabinoid CB1 receptor mediates fear extinction via habituation-like processes. J. Neurosci. 26, 6677–6686 (2006).
Patel, S., Roelke, C. T., Rademacher, D.J., Cullinan, W. E. & Hillard, C. J. Endocannabinoid signaling negatively modulates stress-induced activation of the hypothalamic–pituitary–adrenal axis. Endocrinology 145, 5431–5438 (2004). An important study showing how the endocannabinoids and CB 1 receptors can be involved in the control of stress.
Hohmann, A. G. et al. An endocannabinoid mechanism for stress-induced analgesia. Nature 435, 1108–1112 (2005). Another elegant example of the site- and time-specific activation of the endocannabinoid system following a stressor, and of the therapeutic exploitation of specific inhibitors of endocannabinoid degradation.
Hill, M. N. et al. Involvement of the endocannabinoid system in the ability of long-term tricyclic antidepressant treatment to suppress stress-induced activation of the hypothalamic-pituitary-adrenal axis. Neuropsychopharmacology 31, 2591–2599 (2006).
Moreira, F. A., Kaiser, N., Monory, K. & Lutz, B. Reduced anxiety-like behaviour induced by genetic and pharmacological inhibition of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) is mediated by CB1 receptors. Neuropharmacology 54, 141–150 (2007).
Rubino, T. et al. Role in anxiety behavior of the endocannabinoid system in the prefrontal cortex. Cereb Cortex 5 Oct 2007 (doi:10.1093/cercor/bhm161).
Gobbi, G. et al. Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis. Proc. Natl Acad. Sci. USA 102, 18620–18625 (2005).
Naidu, P. S. et al. Evaluation of fatty acid amide hydrolase inhibition in murine models of emotionality. Psychopharmacology (Berl.) 192, 61–70 (2007).
Degroot, A. & Nomikos, G. G. In vivo neurochemical effects induced by changes in endocannabinoid neurotransmission. Curr. Opin. Pharmacol. 7, 62–68 (2007).
Steiner, M. A. et al. Impaired cannabinoid receptor type 1 signaling interferes with stress-coping behavior in mice. Pharmacogenomics J. 7 Aug 2007 (doi:10.1038/sj.tpj.6500466).
Rademacher, D. J. et al.Effects of acute and repeated restraint stress on endocannabinoid content in the amygdala, ventral striatum, and medial prefrontal cortex in mice. Neuropharmacology 54, 108–116 (2008).
Lutz, B. The endocannabinoid system and extinction learning. Mol. Neurobiol. 36, 92–101 (2007).
Oka, S. et al. Involvement of the cannabinoid CB2 receptor and its endogenous ligand 2-arachidonoylglycerol in oxazolone-induced contact dermatitis in mice. J. Immunol. 177, 8796–8805 (2006).
Mitrirattanakul, S. et al. Site-specific increases in peripheral cannabinoid receptors and their endogenous ligands in a model of neuropathic pain. Pain 126, 102–114 (2006).
Petrosino, S. et al. Changes in spinal and supraspinal endocannabinoid levels in neuropathic rats. Neuropharmacology 52, 415–422 (2007).
Agrawal, N. et al. Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors. Nature Neurosci. 10, 870–879 (2007).
Karsak, M. et al. Attenuation of allergic contact dermatitis through the endocannabinoid system. Science 316, 1494–1497 (2007). The first study that suggests that inhibition of endocannabinoid degradation can be used against allergic contact dermatitis.
Maione, S. et al. Analgesic actions of N-arachidonoyl-serotonin, a fatty acid amide hydrolase inhibitor with antagonistic activity at vanilloid TRPV1 receptors. Br. J. Pharmacol. 150, 766–781 (2007).
Jhaveri, M. D., Richardson, D., Kendall, D. A., Barrett, D. A. & Chapman, V. Analgesic effects of fatty acid amide hydrolase inhibition in a rat model of neuropathic pain. J. Neurosci. 26, 13318–13327 (2006).
Costa, B. et al. Effect of the cannabinoid CB1 receptor antagonist, SR141716, on nociceptive response and nerve demyelination in rodents with chronic constriction injury of the sciatic nerve. Pain 116, 52–61 (2005).
Saez-Cassanelli, J. L., Fontanella, G. H., Delgado-Garcia, J. M. & Carrion, A. M. Functional blockage of the cannabinoid receptor type 1 evokes a κ-opiate-dependent analgesia. J. Neurochem. 103, 2629–2639 (2007).
Lunn, C. A. et al. A novel cannabinoid peripheral cannabinoid receptor-selective inverse agonist blocks leukocyte recruitment in vivo. J. Pharmacol. Exp. Ther. 316, 780–788 (2006).
Croci, T. & Zarini, E. Effect of the cannabinoid CB1 receptor antagonist rimonabant on nociceptive responses and adjuvant-induced arthritis in obese and lean rats. Br. J. Pharmacol. 150, 559–566 (2007).
Kunos, G., Osei-Hyiaman, D., Batkai, S. & Gao, B. Cannabinoids hurt, heal in cirrhosis. Nature Med. 12, 608–610 (2006).
Gary-Bobo, M. et al. Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic syndrome in obese Zucker fa/fa rats. Hepatology 46, 122–129 (2007).
Mendez-Sanchez, N. et al. Endocannabinoid receptor CB2 in nonalcoholic fatty liver disease. Liver Int. 27, 215–219 (2007).
Julien, B. et al. Antifibrogenic role of the cannabinoid receptor CB2 in the liver. Gastroenterology 128, 742–755 (2005).
Teixeira-Clerc, F. et al. CB1 cannabinoid receptor antagonism: a new strategy for the treatment of liver fibrosis. Nature Med. 12, 671–676 (2006). An important study showing how CB 1 and CB 2 receptors play opposing roles in liver fibrosis, and how CB 1 antagonists might be used to treat this disorder.
Batkai, S. et al. Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury. FASEB J. 21, 1788–1800 (2007).
Ofek, O. et al. Peripheral cannabinoid receptor, CB2, regulates bone mass. Proc. Natl Acad. Sci. USA 103, 696–701 (2006).
Idris, A. I. et al. Regulation of bone mass, bone loss and osteoclast activity by cannabinoid receptors. Nature Med. 11, 774–779 (2005).
Guzman, M. Cannabinoids: potential anticancer agents. Nature Rev. Cancer 3, 745–755 (2003).
Di Marzo, V. & Izzo, A. A. Endocannabinoid overactivity and intestinal inflammation. Gut 55, 1373–1376 (2006).
Izzo, A. A. et al. Increased endocannabinoid levels reduce the development of precancerous lesions in the mouse colon. J. Mol. Med. 86, 89–98 (2008).
Sarnataro, D. et al. The cannabinoid CB1 receptor antagonist rimonabant (SR141716) inhibits human breast cancer cell proliferation through a lipid raft-mediated mechanism. Mol. Pharmacol. 70, 1298–1306 (2006).
Massa, F. et al. The endogenous cannabinoid system protects against colonic inflammation. J. Clin. Invest. 113, 1202–1209 (2004).
D'Argenio, G. et al. Up-regulation of anandamide levels as an endogenous mechanism and a pharmacological strategy to limit colon inflammation. FASEB J. 20, 568–570 (2006). The first study showing that endocannabinoid enhancers can be as effective as well-established drugs against experimental colitis.
Croci, T., Landi, M., Galzin, A. M. & Marini, P. Role of cannabinoid CB1 receptors and tumor necrosis factor-α in the gut and systemic anti-inflammatory activity of SR 141716 (rimonabant) in rodents. Br. J. Pharmacol. 140, 115–122 (2003).
Monory, K. et al. The endocannabinoid system controls key epileptogenic circuits in the hippocampus. Neuron 51, 455–466 (2006). An elegant study showing how the endocannabinoids and CB 1 receptors work in a neuron-type-specific way to dampen excitotoxicity.
Maione, S. et al. Elevation of endocannabinoid levels in the ventrolateral periaqueductal grey through inhibition of fatty acid amide hydrolase affects descending nociceptive pathways via both cannabinoid receptor type 1 and transient receptor potential vanilloid type-1 receptors. J. Pharmacol. Exp. Ther. 316, 969–982 (2006).
Lunn, C. A. et al. Biology and therapeutic potential of cannabinoid CB2 receptor inverse agonists. Br. J. Pharmacol. 153, 226–239 (2007).
Miller, A. M. & Stella, N. CB2 receptor-mediated migration of immune cells: it can go either way. Br. J. Pharmacol. 153, 299–308 (2007).
Marsch, R. et al. Reduced anxiety, conditioned fear, and hippocampal long-term potentiation in transient receptor potential vanilloid type 1 receptor-deficient mice. J. Neurosci. 27, 832–839 (2007).
Dinis, P. et al. Anandamide-evoked activation of vanilloid receptor 1 contributes to the development of bladder hyperreflexia and nociceptive transmission to spinal dorsal horn neurons in cystitis. J. Neurosci. 24, 11253–11263 (2004).
Singh Tahim, A., Santha, P. & Nagy, I. Inflammatory mediators convert anandamide into a potent activator of the vanilloid type 1 transient receptor potential receptor in nociceptive primary sensory neurons. Neuroscience 136, 539–548 (2005).
Orliac, M. L., Peroni, R., Celuch, S. M. & Adler-Graschinsky, E. Potentiation of anandamide effects in mesenteric beds isolated from endotoxemic rats. J. Pharmacol. Exp. Ther. 304, 179–184 (2003).
Domenicali, M. et al. Increased anandamide induced relaxation in mesenteric arteries of cirrhotic rats: role of cannabinoid and vanilloid receptors. Gut 54, 522–527 (2005).
Moezi, L. et al. Anandamide mediates hyperdynamic circulation in cirrhotic rats via CB1 and VR1 receptors. Br. J. Pharmacol. 149, 898–908 (2006).
Horvath, G., Kekesi, G., Nagy, E. & Benedek, G. The role of TRPV1 receptors in the antinociceptive effect of anandamide at spinal level. Pain 134, 277–284 (2007).
Hermann, H. et al. Dual effect of cannabinoid CB1 receptor stimulation on a vanilloid VR1 receptor-mediated response. Cell. Mol. Life Sci. 60, 607–616 (2003).
Evans, R. M., Scott, R. H. & Ross, R. A. Chronic exposure of sensory neurones to increased levels of nerve growth factor modulates CB1/TRPV1 receptor crosstalk. Br. J. Pharmacol. 152, 404–413 (2007).
Kathuria, S. et al. Modulation of anxiety through blockade of anandamide hydrolysis. Nature Med. 9, 76–81 (2003). First study demonstrating the potential use of endocannabinoid boosters against anxiety.
Bisogno, T. et al. Arachidonoylserotonin and other novel inhibitors of fatty acid amide hydrolase. Biochem. Biophys. Res. Commun. 248, 515–522 (1998).
Abouabdellah, A. et al. Derivatives of dioxane-2-alkyl carbamates, preparation thereof and application thereof in therapeutics. Patent US20050182130 A1 (2005).
Zhang, D. et al. Fatty acid amide hydrolase inhibitors display broad selectivity and inhibit multiple carboxylesterases as off-targets. Neuropharmacology 52, 1095–1105 (2007).
Piomelli, D. et al. Pharmacological profile of the selective FAAH inhibitor KDS-4103 (URB597). CNS Drug Rev. 12, 21–38 (2006).
Russo, R. et al. The fatty acid amide hydrolase inhibitor URB597 (cyclohexylcarbamic acid 3′-carbamoylbiphenyl-3-yl ester) reduces neuropathic pain after oral administration in mice. J. Pharmacol. Exp. Ther. 322, 236–242 (2007).
Jayamanne, A. et al. Actions of the FAAH inhibitor URB597 in neuropathic and inflammatory chronic pain models. Br. J. Pharmacol. 147, 281–288 (2006).
Holt S., Comelli, F., Costa, B. & Fowler, C. J. Inhibitors of fatty acid amide hydrolase reduce carrageenan-induced hind paw inflammation in pentobarbital-treated mice: comparison with indomethacin and possible involvement of cannabinoid receptors. Br. J. Pharmacol. 146, 467–476 (2005).
Batkai, S. et al. Endocannabinoids acting at cannabinoid-1 receptors regulate cardiovascular function in hypertension. Circulation. 110, 1996–2002 (2004). A complete study showing how endocannabinoids and CB 1 receptors are produced to play a protective function during certain types of hypertension, and how this might be treated by endocannabinoid boosters.
Nucci, C. et al. Involvement of the endocannabinoid system in retinal damage after high intraocular pressure-induced ischemia in rats. Invest. Ophthalmol. Vis. Sci. 48, 2997–3004 (2007). First complete study suggesting the potential use of endocannabinoid enhancers against glaucoma.
Sharkey, K. A. et al. Arvanil, anandamide and N-arachidonoyl-dopamine (NADA) inhibit emesis through cannabinoid CB1 and vanilloid TRPV1 receptors in the ferret. Eur. J. Neurosci. 25, 2773–2782 (2007).
Cross-Mellor, S. K., Ossenkopp, K. P., Piomelli, D. & Parker, L. A. Effects of the FAAH inhibitor, URB597, and anandamide on lithium-induced taste reactivity responses: a measure of nausea in the rat. Psychopharmacology (Berl.) 190, 135–143 (2007).
Patel, S. & Hillard, C. J. Pharmacological evaluation of cannabinoid receptor ligands in a mouse model of anxiety: further evidence for an anxiolytic role for endogenous cannabinoid signaling. J. Pharmacol. Exp. Ther. 318, 304–311 (2006).
Vlachou, S., Nomikos, G. G. & Panagis, G. Effects of endocannabinoid neurotransmission modulators on brain stimulation reward. Psychopharmacology (Berl.) 188, 293–305 (2006).
Solinas, M., Justinova, Z., Goldberg, S. R. & Tanda, G. Anandamide administration alone and after inhibition of fatty acid amide hydrolase (FAAH) increases dopamine levels in the nucleus accumbens shell in rats. J. Neurochem. 98, 408–419 (2006).
Solinas, M. et al. The endogenous cannabinoid anandamide produces Δ-9-tetrahydrocannabinol-like discriminative and neurochemical effects that are enhanced by inhibition of fatty acid amide hydrolase but not by inhibition of anandamide transport. J. Pharmacol. Exp. Ther. 321, 370–380 (2007).
Hansson, A. C. et al. Genetic impairment of frontocortical endocannabinoid degradation and high alcohol preference. Neuropsychopharmacology 32, 117–126 (2007).
Vinod, K. Y., Sanguino, E., Yalamanchili, R., Manzanares, J. & Hungund, B. L. Manipulation of fatty acid amide hydrolase functional activity alters sensitivity and dependence to ethanol. J. Neurochem. 104, 233–243 (2007).
Fegley, D. et al. Characterization of the fatty acid amide hydrolase inhibitor cyclohexyl carbamic acid 3′-carbamoyl-biphenyl-3-yl ester (URB597): effects on anandamide and oleoylethanolamide deactivation. J. Pharmacol. Exp. Ther. 313, 352–358 (2005).
Capasso, R. et al. Fatty acid amide hydrolase controls mouse intestinal motility in vivo. Gastroenterology 129, 941–951 (2005).
Bifulco, M. et al. A new strategy to block tumor growth by inhibiting endocannabinoid inactivation. FASEB J. 18, 1606–1608 (2004). The first study showing that endocannabinoid enhancers can retard cancer growth in vivo.
Suplita, R. L. 2nd, Farthing, J. N., Gutierrez, T. & Hohmann, A. G. Inhibition of fatty-acid amide hydrolase enhances cannabinoid stress-induced analgesia: sites of action in the dorsolateral periaqueductal gray and rostral ventromedial medulla. Neuropharmacology 49, 1201–1209 (2005).
Tzavara, E. T. et al. Endocannabinoids activate transient receptor potential vanilloid 1 receptors to reduce hyperdopaminergia-related hyperactivity: therapeutic implications. Biol. Psychiatry. 59, 508–515 (2006).
Beltramo, M. et al. Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science 277, 1094–1097 (1997).
De Petrocellis, L., Bisogno, T., Davis, J. B., Pertwee, R. G. & Di Marzo, V. Overlap between the ligand recognition properties of the anandamide transporter and the VR1 vanilloid receptor: inhibitors of anandamide uptake with negligible capsaicin-like activity. FEBS Lett. 483, 52–56 (2000).
Ortar G., Ligresti, A., De Petrocellis, L., Morera, E. & Di Marzo, V. Novel selective and metabolically stable inhibitors of anandamide cellular uptake. Biochem. Pharmacol. 65, 1473–1481 (2003).
Lopez-Rodriguez, M. et al. Design, synthesis and biological evaluation of new endocannabinoid transporter inhibitors. Eur. J. Med. Chem. 38, 403–412 (2003).
Fegley, D. et al. Anandamide transport is independent of fatty-acid amide hydrolase activity and is blocked by the hydrolysis-resistant inhibitor AM1172. Proc. Natl Acad. Sci. USA 101, 8756–8761 (2004).
Moore, S. A. et al. Identification of a high-affinity binding site involved in the transport of endocannabinoids. Proc. Natl Acad. Sci. USA 102, 17852–17857 (2005).
Ortar, G. et al. Carbamoyl tetrazoles as inhibitors of endocannabinoid inactivation: a critical revisitation. Eur. J. Med. Chem. 43, 62–72 (2008).
Costa, B. et al. AM404, an inhibitor of anandamide uptake, prevents pain behaviour and modulates cytokine and apoptotic pathways in a rat model of neuropathic pain. Br. J. Pharmacol. 148, 1022–1032 (2006).
La Rana, G. et al. Modulation of neuropathic and inflammatory pain by the endocannabinoid transport inhibitor AM404 [N-(4-hydroxyphenyl)-eicosa-5,8,11,14-tetraenamide]. J. Pharmacol. Exp. Ther. 317, 1365–1371 (2006).
Mitchell, V. A., Greenwood, R., Jayamanne, A. & Vaughan, C. W. Actions of the endocannabinoid transport inhibitor AM404 in neuropathic and inflammatory pain models. Clin. Exp. Pharmacol. Physiol. 34, 1186–1190 (2007).
Chhatwal, J. P., Davis, M., Maguschak, K. A. & Ressler, K. J. Enhancing cannabinoid neurotransmission augments the extinction of conditioned fear. Neuropsychopharmacology 30, 516–524 (2005).
Hill, M. N. & Gorzalka, B. B. Pharmacological enhancement of cannabinoid CB1 receptor activity elicits an antidepressant-like response in the rat forced swim test. Eur. Neuropsychopharmacology 15, 593–599 (2005).
Bortolato, M. et al. Anxiolytic-like properties of the anandamide transport inhibitor AM404. Neuropsychopharmacology 31, 2652–2659 (2006).
Braida, D., Limonta, V., Malabarba, L., Zani, A. & Sala, M. 5-HT1A receptors are involved in the anxiolytic effect of Δ9-tetrahydrocannabinol and AM 404, the anandamide transport inhibitor, in Sprague-Dawley rats. Eur. J. Pharmacol. 555, 156–163 (2007).
Marsicano, G. et al. CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 302, 84–88 (2003).
Karanian, D. A., Brown, Q. B., Makriyannis, A., Kosten, T. A. & Bahr, B. A. Dual modulation of endocannabinoid transport and fatty acid amide hydrolase protects against excitotoxicity. J. Neurosci. 25, 7813–7820 (2005).
Wettschureck, N. et al. Forebrain-specific inactivation of Gq/G11 family G proteins results in age-dependent epilepsy and impaired endocannabinoid formation. Mol. Cell Biol. 26, 5888–5894 (2006).
Fernandez-Espejo, E. et al. Experimental parkinsonism alters anandamide precursor synthesis, and functional deficits are improved by AM404: a modulator of endocannabinoid function. Neuropsychopharmacology 29, 1134–1142 (2004).
Hill, M. N., Kambo, J. S., Sun, J. C., Gorzalka, B. B. & Galea, L. A. Endocannabinoids modulate stress-induced suppression of hippocampal cell proliferation and activation of defensive behaviours. Eur. J. Neurosci. 24, 1845–1849 (2006).
Baker, D. et al. Endocannabinoids control spasticity in a multiple sclerosis model. FASEB J. 15, 300–302 (2001).
Ligresti, A. et al. New potent and selective inhibitors of anandamide reuptake with antispastic activity in a mouse model of multiple sclerosis. Br. J. Pharmacol. 147, 83–91 (2006).
de Lago, E. et al. In vivo pharmacological actions of two novel inhibitors of anandamide cellular uptake. Eur. J. Pharmacol. 484, 249–257 (2004).
de Lago, E. et al. UCM707, an inhibitor of the anandamide uptake, behaves as a symptom control agent in models of Huntington's disease and multiple sclerosis, but fails to delay/arrest the progression of different motor-related disorders. Eur. Neuropsychopharmacol. 16, 7–18 (2006).
Mestre, L. et al. Pharmacological modulation of the endocannabinoid system in a viral model of multiple sclerosis. J. Neurochem. 92, 1327–1339 (2005).
Laine, K. et al. Effects of topical anandamide-transport inhibitors, AM404 and olvanil, on intraocular pressure in normotensive rabbits. Pharm. Res. 18, 494–499 (2001).
Darmani, N. A. et al. Cisplatin increases brain 2-arachidonoylglycerol (2-AG) and concomitantly reduces intestinal 2-AG and anandamide levels in the Least shrew. Neuropharmacology 49, 502–513 (2005).
Solinas, M. et al. Cannabinoid agonists but not inhibitors of endogenous cannabinoid transport or metabolism enhance the reinforcing efficacy of heroin in rats. Neuropsychopharmacology 30, 2046–2057 (2005).
Leung, D., Hardouin, C., Boger, D. L. & Cravatt, B. F. Discovering potent and selective reversible inhibitors of enzymes in complex proteomes. Nature Biotech. 21, 687–691 (2003).
Lichtman, A. H. et al. Reversible inhibitors of fatty acid amide hydrolase that promote analgesia: evidence for an unprecedented combination of potency and selectivity. J. Pharmacol. Exp. Ther. 311, 441–448 (2004).
Alexander, J. P. & Cravatt, B. F. The putative endocannabinoid transport blocker LY2183240 is a potent inhibitor of FAAH and several other brain serine hydrolases. J. Am. Chem. Soc. 128, 9699–9704 (2006).
Oz, M. Receptor-independent effects of endocannabinoids on ion channels. Curr. Pharm. Des. 12, 227–239 (2006).
Starowicz, K., Nigam, S. & Di Marzo, V. Biochemistry and pharmacology of endovanilloids. Pharmacol. Ther. 114, 13–33 (2007).
Lee, J., Di Marzo, V. & Brotchie, J. M. A role for vanilloid receptor 1 (TRPV1) and endocannabinnoid signalling in the regulation of spontaneous and L-DOPA induced locomotion in normal and reserpine-treated rats. Neuropharmacology 51, 557–565 (2006).
Morgese, M. G., Cassano, T., Cuomo, V. & Giuffrida, A. Anti-dyskinetic effects of cannabinoids in a rat model of Parkinson's disease: Role of CB1 and TRPV1 receptors. Exp. Neurol. 208, 110–119 (2007).
Micale, V. et al. Anxiety-like behaviors in wild-type and dopamine D3 receptor knockout (KO) mice: role of endocannabinoids and vanilloid TRPV1 receptors. Program No. 501.25/JJ25. Society for Neuroscience Meeting Planner web site[online], (2007).
Niforatos, W. et al. Activation of TRPA1 channels by the fatty acid amide hydrolase inhibitor 3′-carbamoylbiphenyl-3-yl cyclohexylcarbamate (URB597). Mol. Pharmacol. 71, 1209–1216 (2007).
Guindon, J., Desroches, J. & Beaulieu, P. The antinociceptive effects of intraplantar injections of 2-arachidonoyl glycerol are mediated by cannabinoid CB2 receptors. Br. J. Pharmacol. 150, 693–701 (2007).
Comelli, F., Giagnoni, G., Bettoni, I., Colleoni, M. & Costa, B. The inhibition of monoacylglycerol lipase by URB602 showed an anti-inflammatory and anti-nociceptive effect in a murine model of acute inflammation. Br. J. Pharmacol. 152, 787–794 (2007).
Hillard, C. J., Shi, L., Tuniki, V. R., Falck, J. R. & Campbell, W. B. Studies of anandamide accumulation inhibitors in cerebellar granule neurons: comparison to inhibition of fatty acid amide hydrolase. J. Mol. Neurosci. 33, 18–24 (2007).
Dickason-Chesterfield, A. K. et al. Pharmacological characterization of endocannabinoid transport and fatty acid amide hydrolase inhibitors. Cell. Mol. Neurobiol. 26, 407–423 (2006).
Hogestatt, E. D. et al. Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J. Biol. Chem. 280, 31405–31412 (2005).
Zygmunt, P. M., Chuang, H., Movahed, P., Julius, D. & Hogestatt, E. D. The anandamide transport inhibitor AM404 activates vanilloid receptors. Eur. J. Pharmacol. 396, 39–42 (2000).
Jonsson, K. O. et al. AM404 and VDM 11 non-specifically inhibit C6 glioma cell proliferation at concentrations used to block the cellular accumulation of the endocannabinoid anandamide. Arch. Toxicol. 77, 201–207 (2003).
Kelley, B. G. & Thayer, S. A. Anandamide transport inhibitor AM404 and structurally related compounds inhibit synaptic transmission between rat hippocampal neurons in culture independent of cannabinoid CB1 receptors. Eur. J. Pharmacol. 496, 33–39 (2004).
Ronesi, J., Gerdeman, G. L. & Lovinger, D. M. Disruption of endocannabinoid release and striatal long-term depression by postsynaptic blockade of endocannabinoid membrane transport. J. Neurosci. 24, 1673–1679 (2004).
Ligresti, A. et al. Further evidence for the existence of a specific process for the membrane transport of anandamide. Biochem. J. 380, 265–272 (2004).
Van Gaal, L. F., Rissanen, A. M., Scheen, A. J., Ziegler, O. & Rossner, S. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 365, 1389–1397 (2005).
Despres, J. P., Golay, A. & Sjostrom, L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N. Engl. J. Med. 353, 2121–2134 (2005). A report on an important clinical trial demonstrating the potential use of rimonabant in obese patients not just as a therapeutic aid to reduce body weight.
Pi-Sunyer, F. X., Aronne, L. J., Heshmati, H. M., Devin, J. & Rosenstock, J. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA 295, 761–775 (2006).
Scheen, A. J., Finer, N., Hollander, P., Jensen, M. D. & Van Gaal, L. F. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet 368, 1660–1672 (2006).
Cahill, K. & Ussher, M. Cannabinoid type 1 receptor antagonists (rimonabant) for smoking cessation. Cochrane Database Syst. Rev. 4, CD005353 (2007).
Osei-Hyiaman, D. et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J. Clin. Invest. 115, 1298–1305 (2005). Another important example of a possible role of CB 1 receptors in the aetiology of a liver disorder, and of a potential therapeutic use of CB 1 antagonists.
Pagano, C. et al. The endogenous cannabinoid system stimulates glucose uptake in human fat cells via PI3-kinase and calcium-dependent mechanisms. J. Clin. Endocrinol. Metab. 92, 4810–4819 (2007).
Van Gaal, L., Pi-Sunyer, X, Despres, J. P., McCarthy, C. & Scheen, A. Efficacy and safety of rimonabant for improvement of multiple cardiometabolic risk factors in overweight/obese patients: pooled 1-year data from the Rimonabant in Obesity (RIO) program. Diabetes Care. 31, S229–S240 (2008).
Poirier, B. et al. The anti-obesity effect of rimonabant is associated with an improved serum lipid profile. Diabetes Obes. Metab. 7, 65–72 (2005).
Janiak, P. et al. Blockade of cannabinoid CB1 receptors improves renal function, metabolic profile, and increased survival of obese Zucker rats. Kidney Int. 72, 1345–1357 (2007).
Herling, A. W. et al. CB1 receptor antagonist AVE1625 affects primarily metabolic parameters independently of reduced food intake in Wistar rats. Am. J. Physiol. Endocrinol. Metab. 293, e826–e832 (2007).
Fong, T. M. et al. Antiobesity efficacy of a novel cannabinoid-1 receptor inverse agonist, N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-[[5-(trifluoromethyl)pyridin-2-yl]oxy]propanamide (MK-0364), in rodents. J. Pharmacol. Exp. Ther. 321, 1013–1022 (2007).
Addy, C. et al. Safety, tolerability, pharmacokinetics, and pharmacodynamic properties of taranabant, a novel selective cannabinoid-1 receptor inverse agonist, for the treatment of obesity: results from a double-blind, placebo-controlled, single oral dose study in healthy volunteers. J. Clin. Pharmacol. 7 Feb 2008 (doi:10.1177/0091270008314467).
Rinaldi-Carmona, M. et al. SR147778 [5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide], a new potent and selective antagonist of the CB1 cannabinoid receptor: biochemical and pharmacological characterization. J. Pharmacol. Exp. Ther. 310, 905–914 (2004).
De Marchi, N. et al. Endocannabinoid signalling in the blood of patients with schizophrenia. Lipids Health Dis. 2, 5 (2003).
Giuffrida, A. et al. Cerebrospinal anandamide levels are elevated in acute schizophrenia and are inversely correlated with psychotic symptoms. Neuropsychopharmacology 29, 2108–2114 (2004).
Cao, X. et al. Blockade of cannabinoid type 1 receptors augments the antiparkinsonian action of levodopa without affecting dyskinesias in 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-treated rhesus monkeys. J. Pharmacol. Exp. Ther. 323, 318–326 (2007).
Cohen, C., Perrault, G., Griebel, G. & Soubrie, P. Nicotine-associated cues maintain nicotine-seeking behavior in rats several weeks after nicotine withdrawal: reversal by the cannabinoid (CB1) receptor antagonist, rimonabant (SR141716). Neuropsychopharmacology 30, 145–155 (2005).
Gessa, G. L., Serra, S., Vacca, G., Carai, M. A. & Colombo, G. Suppressing effect of the cannabinoid CB1 receptor antagonist, SR147778, on alcohol intake and motivational properties of alcohol in alcohol-preferring sP rats. Alcohol Alcohol. 40, 46–53 (2005).
Spano, M. S. et al. CB1 receptor agonist and heroin, but not cocaine, reinstate cannabinoid-seeking behaviour in the rat. Br. J. Pharmacol. 143, 343–350 (2004).
De Vries, T. J. et al. A cannabinoid mechanism in relapse to cocaine seeking. Nature Med. 7, 1151–1154 (2001).
Griebel, G., Stemmelin, J. & Scatton, B. Effects of the cannabinoid CB1 receptor antagonist rimonabant in models of emotional reactivity in rodents. Biol. Psychiatry. 57, 261–267 (2005).
Steiner, M. A. et al. Antidepressant-like behavioral effects of impaired cannabinoid receptor type 1 signaling coincide with exaggerated corticosterone secretion in mice. Psychoneuroendocrinology 33, 54–67 (2008).
Costa, B. Rimonabant: more than an anti-obesity drug? Br. J. Pharmacol. 150, 535–537 (2007).
Batkai, S. et al. Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis. Nature Med. 7, 827–832 (2001).
Gaskari, S. A. et al. Role of endocannabinoids in the pathogenesis of cirrhotic cardiomyopathy in bile duct-ligated rats. Br. J. Pharmacol. 146, 315–323 (2005).
Batkai, S. et al. Endocannabinoids acting at CB1 receptors mediate the cardiac contractile dysfunction in vivo in cirrhotic rats. Am. J. Physiol. Heart Circ. Physiol. 293, H1689–H1695 (2007).
Iwamura, H., Suzuki, H., Ueda, Y., Kaya, T. & Inaba, T. In vitro and in vivo pharmacological characterization of JTE-907, a novel selective ligand for cannabinoid CB2 receptor. J. Pharmacol. Exp. Ther. 296, 420–425 (2001).
Rinaldi-Carmona M et al. SR 144528, the first potent and selective antagonist of the CB2 cannabinoid receptor. J. Pharmacol. Exp. Ther. 284, 644–650 (1998).
Ueda, Y., Miyagawa, N., Matsui, T, Kaya, T & Iwamura, H. Involvement of cannabinoid CB2 receptor-mediated response and efficacy of cannabinoid CB2 receptor inverse agonist, JTE-907, in cutaneous inflammation in mice. Eur. J. Pharmacol. 520, 164–171 (2005).
Oka, S. et al. Evidence for the involvement of the cannabinoid CB2 receptor and its endogenous ligand 2-arachidonoylglycerol in 12-O-tetradecanoylphorbol-13-acetate-induced acute inflammation in mouse ear. J. Biol. Chem. 280, 18488–18497 (2005). Perhaps the most convincing study of the possible use of CB 2 antagonists against inflammation.
Bisogno, T. et al. Development of the first potent and specific inhibitors of endocannabinoid biosynthesis. Biochim. Biophys. Acta 1761, 205–212 (2006).
Klein, T. W. Cannabinoid-based drugs as anti-inflammatory therapeutics. Nature Rev. Immunol. 5, 400–411 (2005).
Liu, J. et al. Multiple pathways involved in the biosynthesis of anandamide. Neuropharmacology 54, 1–7 (2008).
Blankman, J. L., Simon, G. M. & Cravatt, B. F. A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chem. Biol. 14, 1347–1356 (2007).
Rouzer, C. A. & Marnett, L. J. Non-redundant functions of cyclooxygenases: oxygenation of endocannabinoids. J. Biol. Chem. 283, 8065–8069 (2008).
Woodward, D. F., Liang, Y. & Krauss, A. H. Prostamides (prostaglandin-ethanolamides) and their pharmacology. Br. J. Pharmacol. 153, 410–419 (2008).
Ryberg, E. et al. The orphan receptor GPR55 is a novel cannabinoid receptor. Br. J. Pharmacol. 152, 1092–1101 (2007).
Oka, S., Nakajima, K., Yamashita, A, Kishimoto, S. & Sugiura, T. Identification of GPR55 as a lysophosphatidylinositol receptor. Biochem. Biophys. Res. Commun. 362, 928–934 (2007).
O'Sullivan, S. E. Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors. Br. J. Pharmacol. 152, 576–582 (2007).
Saario, S. M. et al. Characterization of the sulfhydryl-sensitive site in the enzyme responsible for hydrolysis of 2-arachidonoyl-glycerol in rat cerebellar membranes. Chem. Biol. 12, 649–656 (2005).
Ahn, K. et al. Novel mechanistic class of fatty acid amide hydrolase inhibitors with remarkable selectivity. Biochemistry. 46, 13019–13030 (2007).
Fowler, C. J. et al. Inhibition of fatty acid amidohydrolase, the enzyme responsible for the metabolism of the endocannabinoid anandamide, by analogues of arachidonoyl-serotonin. J. Enzyme Inhib. Med. Chem. 18, 225–231 (2003).
Chang, L. et al. Inhibition of fatty acid amide hydrolase produces analgesia by multiple mechanisms. Br. J. Pharmacol. 148, 102–113 (2006).
Sit, S. Y. et al. Novel inhibitors of fatty acid amide hydrolase. Bioorg. Med. Chem. Lett. 17, 3287–3291 (2007).
Vandevoorde, S. et al. Lack of selectivity of URB602 for 2-oleoylglycerol compared to anandamide hydrolysis in vitro. Br. J. Pharmacol. 150, 186–191 (2007).
The author wishes to thank A. Ligresti and S. Petrosino at the Endocannabinoid Research Group for their help with preparing the manuscript. This article is dedicated to the memory of the highly esteemed scientists and friends Professor Santosh Nigam, who passed away on 2 October 2007, and Professor Michael J. Walker, who passed away 5 January 2008.
The author receives research grants from Allergan, Sanofi–Aventis and GW Pharmaceuticals. He has been in the speakers' bureau for Sanofi–Aventis. The author is co-inventor of several patents on endocannabinoid-based molecules.
Natural lipophilic products from the flower of Cannabis sativa, most of which have a typical bicyclic or tricyclic structure and a common biogenetic origin from olivetol.
- Cannabinoid receptors
G-protein-coupled receptors for Δ9-tetrahydrocannabinol, so far identified in most vertebrate phyla. Two subtypes are known: CB1 and CB2.
Endogenous agonists of cannabinoid receptors in animals.
The major psychotropic component of Cannabis sativa, and one of about 66 'cannabinoids' found in the flowers of this plant.
(2-AG). The second most-studied endocannabinoid after anandamide. It is thought to be the most selective endogenous agonist of cannabinoid 1 and 2 (CB1 and CB2) receptors, and the one most often involved in CB1-mediated retrograde signalling.
A state characterized by an exaggerated drive for food consumption and subsequent enhanced food-intake.
Proliferation of astrocytes in damaged areas of the central nervous system, often associated with anoxic injury and neuronal death, and found in certain brain regions during various neurodegenerative disorders.
- Retrograde signalling
A mechanism whereby a chemical signal is released from the postsynaptic neuron, travels in the synaptic space and activates presynaptic receptors to modulate the release of neurotransmitters, thereby influencing synaptic plasticity.
- Superoxide dismutase 1
(SOD1). One of the enzymes that converts the superoxide anion in oxygen and hydrogen peroxide. Gain-of-function mutations in the Cu,Zn-SOD1 gene are implicated in progressive motor neuron death and paralysis in one form of inherited amyotrophic lateral sclerosis.
- Conditioned fear
An animal defensive behaviour (for example, immobility or 'freezing') that is induced by exposure to aversive stimuli (for example, a non-noxious electrical shock) coupled to a non-aversive one (for example, a light or an acoustic tone). This behaviour can later be reinstated by simply re-exposing the animal to the non-aversive stimulus.
- Non-alcoholic steatosis
Also known as non-alcoholic fatty liver disease, this is the inflammatory accumulation of fat in the liver when this is not due to excessive alcohol use. It is related to insulin resistance.
- Osteoblasts and osteoclasts
Osteoblasts are mononucleate cells that are responsible for bone formation. They produce osteoid, which is composed mainly of type I collagen, and are responsible for mineralization of the osteoid matrix. Bones are constantly being reshaped by osteoblasts, which build bone, for example in its endocortical region, and osteoclasts, which resorb bone, for example in its trabecular region.
- Direct and indirect pathways of locomotor control
Neuronal circuitries in the basal ganglia involving medium spiny GABA (γ-aminobutyric acid)ergic neurons of the dorsal striatum terminating onto other GABAergic neurons in either the substantia nigra reticulata or external layer of the globus pallidus, and ultimately causing stimulation or inhibition of locomotion, respectively.
A six-transmembrane-domain non-selective cation channel that is activated by either physical or chemical stimuli. Stimuli include thermosensation, sensory transduction, taste, flow-sensing, and the detection of obnoxious and irritant compounds.
- Theiler's virus
Theiler's murine encephalo-myelitis virus (TMEV) is a single-stranded RNA picornavirus that persistently infects the mouse central nervous system, recently reclassified into the cardiovirus group. In the wild it produces a gastrointestinal infection that may be complicated by concomitant infection of the nervous system.
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Di Marzo, V. Targeting the endocannabinoid system: to enhance or reduce?. Nat Rev Drug Discov 7, 438–455 (2008). https://doi.org/10.1038/nrd2553
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